The project is conducted as a collaboration among the Tuberculosis Research Section of LCID, NIAID, the Korean Ministry of Health, Welfare and Familys National Masan Tuberculosis Hospital (NMTH) and Yonsei University College of Medicine in the Republic of Korea. These collaborators have worked together to establish the International Tuberculosis Research Center (ITRC) that manages both financial and scientific activities within the laboratory facilities. The hospital is globally unique for its concentration of drug-resistant TB patients (over 700 in-patients per year) and the adjacent center is equipped with a fully functional Biosafety Level 3 laboratory facility. Specific protocol-driven investigations underway include: (1) NIAID 05-I-N069: A Natural History Study of Multidrug-Resistant TB Stains and Host Susceptibility Genes in Korean Patients with Pulmonary TB. This study seeks to characterize MDR and XDR tuberculosis isolates and their contribution to human disease and has over 750 subjects currently enrolled. (2) NIAID 07-I-N041: A Randomized, Double-blind, Placebo-controlled Pilot Study of Metronidazole Combined with Antituberculous Chemotherapy vs. Antituberculous Chemotherapy with Placebo in Subjects with Multi-drug Resistant Pulmonary Tuberculosis. The importance of anaerobic activity in candidate TB drugs is under investigation in this study. In 2009, the trial closed to enrollment after 33 patients enrolled because of concerns about side-effects, but follow up of these subjects and analysis of the data collected continues. (3) NIAID 08-I-N167: A Phase 2a, Randomized, 2 Arm, Open-label, Clinical Trial of the Efficacy of Linezolid Combined with Antituberculous Therapy in Subjects with Extensively Drug-Resistant (XDR) Pulmonary Tuberculosis. The major aim of this study is to evaluate the efficacy, safety and tolerability of one of the drugs of last resort for XDR TB patients, linezolid (LZD, Zyvox, Pfizer). For the moment LZD is infrequently used in TB patients because of its prohibitive cost and adverse-effects but the emergence of XDR TB is spurring doctors into off-label, uncontrolled use in salvage therapy for the few patients that can afford it. This trial opened to enrollment in December 2008 and has enrolled 21 patients with XDR TB in 2010. The interim analysis of the difference in time to sputum culture conversion to tuberculosis negative between the two arms of the study is underway. (4) NIAID 09-I-N061;Pharmacokinetics of Standard First and Second Line anti-TB Drugs in the Lung and Lesions of Subjects Elected for Resection Surgery. This is a multicenter study of the differential penetration of tuberculosis chemotherapeutics into pulmonary tubercular lesions opened to enrollment in 2010 and 2 subjects have been enrolled by Asan Medical Center in Seoul. The study will further define the relationship between pathology and drug penetration in the types of lesions commonly seen in TB patients. The Natural History study of MDR and XDR TB has allowed a number of basic biology questions about the differences in highly drug resistant and drug sensitive tuberculosis to be addressed. This includes a collaborative effort with the Genomic Institute of the Novartis Foundation to sequence a panel of XDR and drug sensitive Mtb isolates to characterize the changes in MDR and XDR isolates that make them unique beyond their mutations in the drug resistance alleles. Several mutations thought to be compensatory and that could restore the fitness of drug resistant strains are being explored. In addition, the role of the presisitor cell phenotype in chronic disease and relaping disease is under investigation. Several collaborations involving new diagnostic tools are also underway that will assess the presence of fragments of Mtb in easily accessible humans samples such as urine and exhaled breath condensate in point of care tests. These have been productive enough for us to add a substudy to the Natural History protocol and enter into a formal discovery effort. In addition, the team has just completed a study of 500 isolates in collaboration with the Foundation for Innovative New Diagnostics (FIND) in Geneva to test the Hain Lifesciences multiplexed line probe assay for detecting resistance to Kanamycin and other aminoglycosides and the major fluoroquinolones in order to detect XDR TB more rapidly. This data was collected to support global approval of this test by the World Health Organization's Strategic Technical Advisory Committee (STAG) for implementation in disease-endemic countries. Similar efforts are being made to detect Mtb drug resistance alleles in sputum samples so that effective therapy can be prescribed at the initiation of therapy rather than 3 to 4 months after drug treatment begins.